The present invention relates to a novel compound, namely 5-cyano-10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine of formula (VI) 
which is a starting compound for the preparation of two important pharmaceutically active compounds, respectively carbamazepine and oxcarbamazepine.
Furthermore, the invention relates to a process for the preparation of 5-cyano-10-hydroxy-10,11-dihydro-5H-dibenz[b,f]azepine, of formula (VI) characterized in that novel intermediates of general formula 
wherein X is a halogen atom or an AcO group, wherein Ac is an aliphatic or aromatic acyl residue, are subjected to hydrolysis.
Preferably, when X is a halogen atom, this is bromine or chlorine; when X is an AcO group, Ac is a C1-C5 aliphatic acyl residue, or a benzoyl, phenylacetyl, 2- or 3-phenyl-propionyl residue optionally substituted on the benzene ring with one or more C1-C4 alkyl or alkoxy groups or with one or more halogen atoms. Most preferably, Ac is an acetyl or benzoyl residue.
The invention also relates to the novel intermediates having the general formula defined above, particularly those wherein X is bromine, chlorine, acetyloxy and benzoyloxy.
In a preferred embodiment, the process according to the invention is characterized in that 5-cyano-10,11-dihydro-5H-dibenz[b,f]azepine of formula (I) is selectively halogenated or xe2x80x9coxygenatedxe2x80x9d at the 10-position through a radical mechanism, and 5-cyano-10-bromo-10,11-dihydro-5H-dibenz[b,f]azepine of formula (II) (X=Br), or 5-cyano-10-chloro-10,11-dihydro-5H-dibenz[b,f]azepine of formula (III) (X=Cl), or 5-cyano-10-benzoyloxy-10,11-dihydro-5H-dibenz[b,f]azepine of formula (IV) (X=OCOPh), or 5-cyano-10-acetoxy-10,11-dihydro-5H-dibenz[b,f]azepine (V) (X=OCOCH3) are hydrolyzed, the final product of formula (VI) being recovered in a pure form.
The process of the invention is represented in the following reaction scheme: 
As already mentioned, the compounds (II), (III), (IV), (V) and (VI) are novel, and the compound (VI) prepared according to the present invention is a simple, inexpensive precursor for the compounds 5-cyano-10-oxo-10,11-dihydro-5H-dibenz[b,f]azepine of formula (VII), 5-carbamoyl-10-oxo-10,11 -dihydro-5H-dibenz[b,f]azepine (oxcarbamazepine) of formula (VIII) and 5-carbamoyl-5H-dibenz[b,f]azepine (carbamazepine) of formula (IX). 
All the known processes for the preparation of compound (VIII) use 5H-dibenz[b,f]azepine unsaturated derivatives as precursors. Thus, according to DE 2,011,087, (VIII) is prepared by hydrolysis of 10-methoxy-5H-dibenz[b,f]azepine, whereas according to BE 597,793 it is prepared by hydrolysis of 10-bromo-5-acetyl-5H-dibenz[b,f]azepine, subsequent phosgenation and treatment with ammonia. JP S1 73.066 discloses the preparation of (VIII) by hydrolysis of 10-chloro-5-carbamoyl-5H-dibenz[b,f]azepine, and JP 79.138.588 by epoxidation of 5-carbamoyl-5H-dibenz[b,f]azepine, and salt-catalyzed rearrangement; according to EP 0,028,028, (VIII) is prepared from 10-nitro-5-cyano-5H-dibenz[b,f]azepine by reduction and hydrolysis. Compared with these preparation methods, which start from very expensive 9,10-unsaturated precursors and are characterized by a high number of steps, the process of the invention only comprises a limited number of steps, which can be carried out under very mild conditions with easy recycle of intermediate solvents and reagents, requires no costly reagents and provides highly pure compounds of formula (VI), (VIII) and (IX), in high yields. Furthermore, the precursor compound (I) has low cost and very good stability.
Radical functionalizations of polyalkylaromatic compounds at the side chain (halogenations and oxygenations) are known to produce complex mixtures of products with positional and substrate selectivity problems, in particular between precursors and mono-functionalized products, so that the latter are difficult to obtain with high conversions and in good yields. The most used agents are N-bromoamides, which anyway never provide selectivities above 80-85%. Even less selective are benzyl chlorination or benzyl oxygenation agents.
It has now surprisingly been found that radical bromination of the compound of formula (I) (and, to a lower, but still interesting, extent, chlorination and acyloxylation) under suitable conditions provide high selectivity, thus obtaining mono-functionalization compounds (respectively (II) by bromination, (III) by chlorination, (IV) by benzoyloxylation and (V) by acetoxylation) in very good yields, by making use of slight molar excesses of oxidizing agents (1.02-1.1), at the same time easily recovering compounds (II), (III), (IV) and (V) or subjecting directly the resulting crude compounds to hydrolysis to obtain the compound of formula (VI).
According to the present invention, compound (I) is brominated with N-bromoamides, such as N-bromo-succinimide, N,Nxe2x80x2-dibromohydantoin, and the like, under radical initiation by means of peroxide thermal radical initiators (such as dibenzoylperoxide, di-t-butylperoxalate, and the like) or of azo-derivatives (such as azobisisobutyronitrile, azobis-1-cyclohexylnitrile, and the like), or by photochemical initiation (irradiation in the visible 400-800 nm). The reaction is carried out in a suitable solvent, which is stable under the halogenation conditions and induces no undesired side-reactions. Particularly suitable are aliphatic and aromatic halo solvents, such as CCl4, CHCl3, CH2Cl2, chlorobenzene, and the like. The bromoamide is used in a 1.02-1.2 molar ratio to compound (I), preferably 1.05-1.1. The ratio of starting material to solvent amount (weight/volume) can range within wide limits, 1:3 to 1:15 ratios being preferred. The reaction temperature is selected in the range of 0-150xc2x0 C., preferably 20-80xc2x0 C. Compound (II) can be isolated from the reaction mixture, or, preferably, it is directly hydrolyzed to obtain compound (VI).
The latter procedure is particularly convenient in that it provides a controlled hydrolysis of compound (II) and allows to recover compound (VI) from the organic phase, and hydrobromic acid and N-bromoamide from the aqueous phase, which is economically and environmentally important in that the N-bromoamide can be obtained again by oxidation of the aqueous phase, for example with alkali bromates.
According to the invention the compound (II) (isolated or crude) can in fact be hydrolyzed in an organic-aqueous diphasic system to give compound (VI). For this purpose, compound (II) is dissolved in a suitable inert organic solvent with medium-low polarity, in the above indicated ratio (or the solution resulting from bromination is used) and the resulting solution is thoroughly stirred with water. The volume ratio of organic solvent to water ranges from 1:1 to 1:10, whereas the temperature is selected from 0 to 120xc2x0 C., preferably 40-80xc2x0 C. Hydrolysis is continued until no more than 1-2% of (II) remains (HPLC or TLC), and it can be accelerated by the presence of polar organic compounds, such as ethers or amides, particularly polyoxyethylenes (PEG) with M.W. 300-10.000. The organic phase is separated and dried, to recover compound (VI) by conventional techniques, which compound may optionally be recrystallized from mixtures of aromatic and aliphatic solvents, esters, ethers or ketones.
The benzyl chlorination reaction under radical conditions can be carried out, according to the invention, either by use of chlorinating agents such as Cl2, SO2Cl2 or N-chloroamides in the presence of thermal initiators such as those mentioned above for the bromination, or by photochemical irradiation (in the visible, 400-800 nm or nears UV). Compound (III) can be separated from by-products in useful yields, although with lower selectivity than in case of bromination. Compound (III) can be hydrolyzed to (VI) in similar solvents and ratios to those used for the bromo-derivative, at temperatures ranging from 80 to 120xc2x0 C.
According to the invention, the benzyl acyloxylation reaction can be effected in organic solutions of compound (I) by decomposition (thermal, photochemical or with suitable metal salts) of diacylperoxides, such as dibenzoylperoxide or diacetylperoxide, or peresters such as t-butyl perbenzoate or t-butylperacetate, in the presence of catalytic amounts of copper(II) carboxylates having the same acid residue as the peroxocompound. Particularly suitable are aliphatic and aromatic halo solvents, such as CCl4, CHCl3, CH2Cl2, chlorobenzene, and the like. The peroxocompound is used in a 1.0-1.3 molar ratio to (I), preferably 1.1-1.2. The starting material to solvent ratio (weight/volume) can range within wide limits, 1:3 to 1:15 ratios being preferred. The reaction temperature is selected within the range of 0-120xc2x0 C., preferably 30-90xc2x0 C. The acyloxylated compound can be isolated or, preferably, it can be directly hydrolyzed to give compound (VI).
According to the invention, compound (VIII) can be obtained from compound (VII) by hydrolysis with acid agents according to the known technique (for example according the teachings of EP 0,028,028). Compound (VII) can, in its turn, be obtained from compound (VI) by oxidation with known oxidizing agents for the transformation of alcohols into ketones. In particular, it has surprisingly been found that the conversion of (VI) into (VII) is very selective and efficient when using an organic/aqueous diphasic system containing sodium hypochlorite at pH ranging from 8 to 9, in the presence of catalytic amounts (0.2-10%) of a stable nitroxide, such as 2,2,6,6-tetramethylpiperidine nitroxide (TEMPO) or 4-oxy-2,2,6,6-tetramethylpiperidine nitroxide. The used solvents are organic compounds stable to these oxidizers, in particular aliphatic and aromatic halo solvents, such as CCl4, CHCl3, CH2Cl2, chlorobenzene, and the like, or poorly water-soluble ethers, (methyl-tert-butyl ether or di-n-butyl ether). Sodium hypochlorite is used in concentrations ranging from 5 to 15%, and pH is adjusted with acid agents, such as KHSO4, oxalic acid, dichloracetic acid, and the like. The reaction temperature is selected in the range from xe2x88x9210 to +60xc2x0 C., preferably 0-20xc2x0 C. Compound (VII) can be recovered in high yield and purity by separation of the organic phase and evaporation of the solvent, or by recrystallization from esters, such as ethyl acetate, or ketones, such as acetone or methyl ethyl ketone.
According to the invention, compound (IX) can be prepared starting from compound (VI) in a single step comprising the elimination and acid or alkali hydrolysis reactions. Alternatively, compound (IX) can be obtained by dehydration of (VIII) to give 5-cyano-5H-dibenz[b,f]azepine, and subsequent hydrolysis of the latter with acid agents.